Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Objective To assess the prospective associations between consumption of ultra-processed foods and risk of cardiovascular diseases. Design Population based cohort study. Setting NutriNet-Sante cohort, France 2009-18. Participants 105 159 participants aged at least 18 years. Dietary intakes were collected using repeated 24 hour dietary records (5.7 for each participant on average), designed to register participants’ usual consumption of 3300 food items. These foods were categorised using the NOVA classification according to degree of processing. Main outcome measures Associations between intake of ultra-processed food and overall risk of cardiovascular, coronary heart, and cerebrovascular diseases assessed by multivariable Cox proportional hazard models adjusted for known risk factors. Results During a median follow-up of 5.2 years, intake of ultra-processed food was associated with a higher risk of overall cardiovascular disease (1409 cases; hazard ratio for an absolute increment of 10 in the percentage of ultra-processed foods in the diet 1.12 (95% confidence interval 1.05 to 1.20); P Conclusions In this large observational prospective study, higher consumption of ultra-processed foods was associated with higher risks of cardiovascular, coronary heart, and cerebrovascular diseases. These results need to be confirmed in other populations and settings, and causality remains to be established. Various factors in processing, such as nutritional composition of the final product, additives, contact materials, and neoformed contaminants might play a role in these associations, and further studies are needed to understand better the relative contributions. Meanwhile, public health authorities in several countries have recently started to promote unprocessed or minimally processed foods and to recommend limiting the consumption of ultra-processed foods. Study registration ClinicalTrials.gov NCT03335644.

https://www.bmj.com/content/bmj/365/bmj.l1451.full.pdf

Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé)

Importance Ultraprocessed foods (UPF) are widespread in Western diets. Their consumption has been associated in recent prospective studies with increased risks of all-cause mortality and chronic diseases such as cancer, cardiovascular diseases, hypertension, and dyslipidemia; however, data regarding diabetes is lacking. Objective To assess the associations between consumption of UPF and risk of type 2 diabetes (T2D). Design, Setting, and Participants In this population-based prospective cohort study, 104 707 participants aged 18 years or older from the French NutriNet-Sante cohort (2009-2019) were included. Dietary intake data were collected using repeated 24-hour dietary records (5.7 per participant on average), designed to register participants' usual consumption for more than 3500 different food items. These were categorized according to their degree of processing by the NOVA classification system. Main Outcomes and Measures Associations between UPF consumption and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). Results A total of 104 707 participants (21 800 [20.8%] men and 82 907 [79.2%] women) were included. Mean (SD) baseline age of participants was 42.7 (14.5) years. Absolute T2D rates in the lowest and highest UPF consumers were 113 and 166 per 100 000 person-years, respectively. Consumption of UPF was associated with a higher risk of T2D (multi-adjusted hazard ratio [HR] for an absolute increment of 10 in the percentage of UPF in the diet, 1.15; 95% CI, 1.06-1.25; median follow-up, 6.0 years; 582 252 person-years; 821 incident cases). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet, for other metabolic comorbidities (HR, 1.13; 95% CI, 1.03-1.23), and for weight change (HR, 1.13; 95% CI, 1.01-1.27). The absolute amount of UPF consumption (grams per day) was consistently associated with T2D risk, even when adjusting for unprocessed or minimally processed food intake (HR for a 100 g/d increase, 1.05; 95% CI, 1.02-1.08). Conclusions and Relevance In this large observational prospective study, a higher proportion of UPF in the diet was associated with a higher risk of T2D. Even though these results need to be confirmed in other populations and settings, they provide evidence to support efforts by public health authorities to recommend limiting UPF consumption. Trial Registration ClinicalTrials.gov Identifier:NCT03335644

/pdf/ultraprocessed-food-consumption-and-risk-of-type-2-diabetes-4alotsupfd.pdf

Ultraprocessed Food Consumption and Risk of Type 2 Diabetes Among Participants of the NutriNet-Santé Prospective Cohort

Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) are commonly recommended anti-HER2 target agents by the U.S. Food and Drug Administration. This review summarizes the most significant and updated research on clinical scenarios related to HER2-positive breast cancer management in order to revise the guidelines of everyday clinical practices. In this article, we present the data on anti-HER2 clinical research of neoadjuvant, adjuvant, and metastatic studies from the past 2 decades. We also highlight some of the promising strategies that should be critically considered. Lastly, this review lists some of the ongoing clinical trials, findings of which may soon be available.

Targeted therapeutic options and future perspectives for HER2-positive breast cancer.

Summary Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease The primary endpoint was progression-free survival according to masked independent central review Efficacy and safety were assessed in all patients who received at least one dose of the study drugs Results presented here are from a prespecified interim analysis This study is registered with ClinicalTrialsgov, NCT03080805 Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy Funding Jiangsu Hengrui Medicine and National Key R&D Program of China Translations For the Chinese translation of the abstract see Supplementary Materials section

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30702-6.pdf

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial

Elizabeth Gourd

Papers

EMA restricts use of anti-PD-1 drugs for bladder cancer.

Pyrotinib shows activity in metastatic breast cancer.

Lung cancer control in the UK hit badly by COVID-19 pandemic.

Nivolumab plus ipilimumab in metastatic colorectal cancer.

PEGPH20 for metastatic pancreatic ductal adenocarcinoma